alpha2-Agonists for Acute Alcohol Withdrawal

Summary

To our knowledge, this is the first comprehensive review to examine the role of α₂-agonists, including dexmedetomidine, in the treatment of alcohol withdrawal. The influence of noradrenergic neurotransmission in alcohol withdrawal has been established; however, the benefits of solely targeting this neurotransmitter or neuronal pathway are limited. Clinical trials with clonidine and case reports with dexmedetomidine have reported benefit with this drug class in ameliorating the symptoms of sympathetic overdrive that are part of the alcohol withdrawal symptom constellation. Although α₂-agonists provide an additional pharmacologic agent in the clinician's armamentarium, they offer no benefit in the prevention or treatment of alcohol withdrawal seizures or delirium tremens. Therefore, we believe that the only role for α₂-agonists is as adjunctive medication to benzodiazepines.

Positive findings from case reports on use of dexmedetomidine, coupled with its ease of use, safety profile, and lack of intubation requirements, make this medication a valuable choice for alcohol withdrawal in the ICU. Lastly, because dexmedetomidine offers advantages over medications currently used in the ICU, further study is merited to fully elicit its place in the alcohol withdrawal treatment algorithm.

Table 1. Summary of Prospective, Randomized Clinical Trials of Clonidine for Treatment of Alcohol Withdrawal
Reference	Study Design/Duration	Patients Randomized (N)/Patients Included in Analyses (n)	Treatment Arms	Primary Efficacy Measures	Results
Bjorkqvist (1975)¹⁴	R, DB, PC 4 days	60/60	Clonidine 0.15 mg up to 3 times daily vs placebo Adjunctive diphenhydramine, metaqualone, chlorproma-zine, and diphenylhydantoin allowed	Self-rated and nurse observer–rated symptoms of alcohol withdrawal	Self-rated and nurse observer–rated symptoms of alcohol withdrawal both significantly reduced with clonidine vs placebo on day 2 of treatment (p < 0.025 and p < 0.01, respectively)
Walinder (1981)¹⁵	R, OL, PG 7 days	26/19	Clonidine 4 μg/kg twice daily vs standard care (carbamazepine 200 mg 3–4 times daily plus chlorprothixene or dixyrazine 50 mg 3 times daily) Adjunctive low-dose benzodiazepines allowed	Clinician ratings of alcohol withdrawal symptoms on the Comprehensive Psychopathological Rating Scale	No significant difference in clinician ratings of alcohol withdrawal between clonidine and standard care (p value not reported)
Manhem (1985)¹⁶	R, DB, PG 4 days	20/17	Clonidine 0.15–0.3 mg every 6 h vs chlormethiazole 500–1000 mg every 6 h All pts. received carbamazepine 200 mg twice daily	BP; pulse; nurse observer–rated symptoms of alcohol withdrawal	BP and pulse lower with clonidine vs chlormethiazole (p < 0.05 for both); no significant difference in nurse observer ratings of alcohol withdrawal between clonidine and chlormethiazole (overall p value not reported)
Baumgartner (1987)¹⁸	R, DB, PG 4 days	61/47	Clonidine 0.2–0.6 mg daily vs chlordiazepoxide 50–150 mg daily	Clinician-rated symptoms of alcohol withdrawal	Lower overall clinician-rated symptoms of alcohol withdrawal with clonidine vs chlordiazepoxide (overall p value not reported), driven by differences in BP and pulse between groups
Baumgartner (1991)¹⁹	R, DB, PG 4 days	50/43	Clonidine 0.2 mg oral load plus two 0.2 mg/24 h transdermal patches (1 patch removed on day 3 and the other on day 4) vs chlordiazepoxide 50–150 mg daily	Clinician ratings of alcohol withdrawal symptoms on the Alcohol Withdrawal Assessment Scale	Lower mean clinician-rated symptoms of alcohol withdrawal with clonidine vs chlordiazepoxide (p < 0.03), driven by differences in BP, pulse, and anxiety ratings between groups
Robinson (1989)²⁰	R, DB, PG 4 days	32/32	Clonidine 0.3–0.9 mg vs chlormethiazole 1000–3000 mg	Alcohol withdrawal to an asymptomatic stage or symptomatic/physical deterioration requiring study withdrawal	50% of pts. in the clonidine group were withdrawn from the trial due to clinical deterioration vs none in the chlormethiazole group (p = 0.002)
Adinoff (1994)²¹	R, DB, PC, PG 4 days	25/25	Repeated doses of clonidine 0.1 mg, alprazolam 1 mg, diazepam 10 mg, or placebo	Number of doses required to achieve a CIWA-Ar score of ≤5	Fewer doses of alprazolam were required to achieve CIWA-Ar ≤5 vs clonidine (p < 0.04) and placebo (p < 0.03); clonidine did not separate from placebo (p value not reported)
Spies (1996)²³	R, RB, PG Unspecified duration, up to 17 days	180/159	Flunitrazepam/clonidine, chlormethiazole/haloperidol, or flunitrazepam/haloperidol (iv bolus followed by continuous iv infusion at varying doses to achieve a CIWA-Ar score <10)	Duration of controlled or assisted mechanical ventilation and frequency of major complications	Longer duration of mechanical ventilation with chlormethiazole/haloperidol (p = 0.03), cardiac complications more frequent with with flunitrazepam/clonidine (p = 0.005), and pneumonia less frequent with flunitrazepam/clonidine (p = 0.04) vs other drugs

Table 1. Summary of Prospective, Randomized Clinical Trials of Clonidine for Treatment of Alcohol Withdrawal

Reference

Study Design/Duration

Patients Randomized (N)/Patients Included in Analyses (n)

Treatment Arms

Primary Efficacy Measures

Results

Bjorkqvist (1975)¹⁴

R, DB, PC 4 days

60/60

Clonidine 0.15 mg up to 3 times daily vs placebo
Adjunctive diphenhydramine, metaqualone, chlorproma-zine, and diphenylhydantoin allowed

Self-rated and nurse observer–rated symptoms of alcohol withdrawal

Self-rated and nurse observer–rated symptoms of alcohol withdrawal both significantly reduced with clonidine vs placebo on day 2 of treatment (p < 0.025 and p < 0.01, respectively)

Walinder (1981)¹⁵

R, OL, PG 7 days

26/19

Clonidine 4 μg/kg twice daily vs standard care (carbamazepine 200 mg 3–4 times daily plus chlorprothixene or dixyrazine 50 mg 3 times daily)
Adjunctive low-dose benzodiazepines allowed

Clinician ratings of alcohol withdrawal symptoms on the Comprehensive Psychopathological Rating Scale

No significant difference in clinician ratings of alcohol withdrawal between clonidine and standard care (p value not reported)

Manhem (1985)¹⁶

R, DB, PG 4 days

20/17

Clonidine 0.15–0.3 mg every 6 h vs chlormethiazole 500–1000 mg every 6 h
All pts. received carbamazepine 200 mg twice daily

BP; pulse; nurse observer–rated symptoms of alcohol withdrawal

BP and pulse lower with clonidine vs chlormethiazole (p < 0.05 for both); no significant difference in nurse observer ratings of alcohol withdrawal between clonidine and chlormethiazole (overall p value not reported)

Baumgartner (1987)¹⁸

R, DB, PG 4 days

61/47

Clonidine 0.2–0.6 mg daily vs chlordiazepoxide 50–150 mg daily

Clinician-rated symptoms of alcohol withdrawal

Lower overall clinician-rated symptoms of alcohol withdrawal with clonidine vs chlordiazepoxide (overall p value not reported), driven by differences in BP and pulse between groups

Baumgartner (1991)¹⁹

R, DB, PG 4 days

50/43

Clonidine 0.2 mg oral load plus two 0.2 mg/24 h transdermal patches (1 patch removed on day 3 and the other on day 4) vs chlordiazepoxide 50–150 mg daily

Clinician ratings of alcohol withdrawal symptoms on the Alcohol Withdrawal Assessment Scale

Lower mean clinician-rated symptoms of alcohol withdrawal with clonidine vs chlordiazepoxide (p < 0.03), driven by differences in BP, pulse, and anxiety ratings between groups

Robinson (1989)²⁰

R, DB, PG 4 days

32/32

Clonidine 0.3–0.9 mg vs chlormethiazole 1000–3000 mg

Alcohol withdrawal to an asymptomatic stage or symptomatic/physical deterioration requiring study withdrawal

50% of pts. in the clonidine group were withdrawn from the trial due to clinical deterioration vs none in the chlormethiazole group (p = 0.002)

Adinoff (1994)²¹

R, DB, PC, PG 4 days

25/25

Repeated doses of clonidine 0.1 mg, alprazolam 1 mg, diazepam 10 mg, or placebo

Number of doses required to achieve a CIWA-Ar score of ≤5

Fewer doses of alprazolam were required to achieve CIWA-Ar ≤5 vs clonidine (p < 0.04) and placebo (p < 0.03); clonidine did not separate from placebo (p value not reported)

Spies (1996)²³

R, RB, PG Unspecified duration, up to 17 days

180/159

Flunitrazepam/clonidine, chlormethiazole/haloperidol, or flunitrazepam/haloperidol (iv bolus followed by continuous iv infusion at varying doses to achieve a CIWA-Ar score <10)

Duration of controlled or assisted mechanical ventilation and frequency of major complications

Longer duration of mechanical ventilation with chlormethiazole/haloperidol (p = 0.03), cardiac complications more frequent with with flunitrazepam/clonidine (p = 0.005), and pneumonia less frequent with flunitrazepam/clonidine (p = 0.04) vs other drugs